5-HT7 receptor and blood pressure regulation

项目摘要 尽管进行了深入的研究，但血压调节障碍--高血压和 低血压仍然是严重、普遍和棘手的医学问题。有效的相对较少 在过去的几十年里，血压失调的管理方法已经出现， 需要战略。5-羟色胺（5-hydroxytryptamine，5-HT）是最早发现于心血管疾病的血清素。 但内源性5-HT在心血管生理和病理生理中的作用尚不清楚 定义了这是因为5-HT在CV系统内具有复杂的作用，其由几种不同的细胞因子介导。 受体亚型当考虑血压终点时，这一点得到了很好的说明。取决于 注射部位、给药剂量和靶向受体，肾上腺素能药物可以提高或升高 血压.在CV系统中表达的5-HT受体（5-HT 1B/1D、5-HT 2A、5-HT 3、5-HT 4和5-HT 2A）中， HT 7受体），5-HT对5-HT 7受体具有最高的亲和力。由于内源性血浆和组织 估计5-HT水平在低nM范围内，内源性5-HT可能主要作用于5-HT 7 感受器来影响血压的变化。先前的研究支持这一关于急性 （秒至分钟）外源性5-HT的作用。在过去的十年里，我们已经证明了这一点， 外源性5-HT的慢性（数天至数周）血压效应，使用传统药理学 方法和我们开发的一种新的遗传模型（5-HT 7受体敲除大鼠）。因此，我们现在 很好地定位于测试内源性5-HT改变正常和高血压患者血压的总体假设， 主要通过外周血管系统中5-HT 7受体的活化而引起的病理生理状况， 最终目标是利用5-HT 7受体药理学来治疗血压调节障碍。 我们提出通过三个具体目的来检验这一假设：目的1：检验5-HT 7受体 目的2：验证血管5-HT 7受体是血管内皮细胞的一种重要受体的假说。 目的3：为了测试在正常大鼠中内源性（组成性）激活以降低血压， 在具有增加的5-HT释放或形成的大鼠模型中产生的低血压是5-HT 7受体依赖性的。 提出了一系列综合技术，这是我们联合实验室的优势。 这些包括等长收缩的分离组织浴测量， 包括组成性活动的概念，以及测量心血管参数的无线电遥测， 清醒的老鼠我们的专业知识与新获得的内脏静脉成像能力相结合， 和动脉直径。该项目旨在发现5-HT的独特能力， 通过5-HT 7受体选择性地激活静脉（和可能的微）循环， 压力，一个有前途的治疗领导许多心血管疾病。

Project Summary Despite intensive investigation, disorders of blood pressure regulation -- both hypertension and hypotension -- continue to be serious, widespread and intractable medical problems. Relatively few effective approaches to management of blood pressure dysregulation have emerged over the last few decades so novel strategies are needed. Serotonin (5-hydroxytryptamine, 5-HT) was first discovered in the cardiovascular system, but the roles of endogenous 5-HT in cardiovascular physiology and pathophysiology are not well defined. This is because 5-HT has complex effects within the CV system that are mediated by several distinct receptor subtypes. This is well-illustrated when considering the endpoint of blood pressure. Depending on the site of injection, the dose administered, and the receptor targeted, serotonergic drugs can raise or elevate blood pressure. Of the 5-HT receptors expressed in the CV system (the 5-HT 1B/1D, 5-HT2A, 5-HT3, 5-HT4 and 5- HT7 receptor), 5-HT has the highest affinity for the 5-HT7 receptor. Since endogenous plasma and tissue levels of 5-HT are estimated to be in the low nM range, endogenous 5-HT likely acts primarily at 5-HT7 receptors to effect changes in blood pressure. Previous studies support this conjecture regarding the acute (seconds to minutes) effects of exogenous 5-HT. Over the last decade, we have proven this is also true for the chronic (days to weeks) blood pressure effects of exogenous 5-HT, using both traditional pharmacological approaches and a new genetic model (5-HT7 receptor knockout rat) that we developed. Therefore, we now are well-positioned to test the overall hypothesis that endogenous 5-HT modifies blood pressure in normal and pathophysiological conditions primarily by activation of 5-HT7 receptors in the peripheral vasculature, with the ultimate goal of capitalizing on 5-HT7 receptor pharmacology to treat disorders of blood pressure regulation. We propose to test this hypothesis via three Specific Aims: Aim 1: To test the hypothesis that 5-HT7 receptor activation dilates the microcirculation; Aim 2: To test the hypothesis that the vascular 5-HT7 receptor is (constitutively) activated endogenously to lower blood pressure in normal rats; and Aim 3: To test that the hypotension created in rat models with increased release or formation of 5-HT is 5-HT7 receptor-dependent. An integrated series of techniques that are the strengths of our combined laboratories are proposed. These include isolated tissue bath measurement of isometric contraction, measures of receptor activation that include the concept of constitutive activity, and radiotelemetry to measure cardiovascular parameters in conscious rats. Our established expertise is combined with newly gained abilities to image splanchnic venous and arterial diameters in the whole rat. This project is aimed to discover the unique ability of 5-HT to selectively activate the venous (and possibly micro) circulation through the 5-HT7 receptor and reduce blood pressure, a promising therapeutic lead for numerous cardiovascular disorders.